Protein kinase is one of the largest families in human enzymes, and more than 500 kinds of protein kinases have been identified in the human body to date. These protein kinases modulate the activities of particular proteins by transferring phosphate groups to the proteins, and then control complex signaling pathways. Aberrant activities of protein kinases are correlated with many diseases including cancers, autoimmune disorders, and so on. Because of the essential role of protein kinases in signaling pathways and the correlation between the kinase activities and many diseases, kinase inhibitors have now become a hot topic for the research and discovery of new chemical entities.
BTK (Bruton's tyrosine kinase) is a non-receptor tyrosine kinase of TEC family BTK is an essential media of B cell receptor (BCR) signaling pathway and it is a key modulator of early B cell development, and activation, signaling and survival of mature B cells. Thus, BTK inhibitors can be used for treating diseases associated with aberrant activation of B cells, for example, autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus, etc. The efficacy for treating autoimmune diseases by BTK inhibitors has been preliminary demonstrated in the preclinical animal models (Honigberg, L. A. et al, Proceedings of the National Academy of Sciences of the United States of America, 2010, 107, 13075-13080). Besides B cells, there are experimental evidences showing that BTK also takes part in the signal pathways of monocytes, macrophages, neutrophils and mast cells. BTK inhibitors can depress FcγR-induced release of cytokines including TNFa, IL-1β and IL-6, from monocytes and macrophages, and can also reduce the FcγR-induced degranulation of mast cells (Chang B. Y. et al, Arthritis Research & Therapy, 2011, 13, R115).
The B cell receptor (BCR)-mediated signaling pathway is vital to the survival of many lymphomas. As a key kinase in the BCR pathway, BTK is therefore a potential therapeutic target of lymphomas. In clinical trials, BTK inhibitors show significant effects in the treatment of chronic lymphocytic leukemia (CLL). BTK inhibitors also exhibit significant effects on other lymphomas such as diffused large B-cell lymphoma and mantle cell lymphoma, etc. (Buggy, J. J. et al, International Reviews of Immunology, 2012, 31, 119-132).
Janus kinases are essential tyrosine kinases for modulating the cellular function of lymphatic and hematopoietic cells. Janus kinases include four known members, which are JAK1, JAK2, JAK3 and TYK2, respectively, and wherein JAK3 (Janus tyrosine kinase 3) is mainly expressed in lymphocytes and natural killer cells. JAK3 is constitutively bound to the common γc chain, which is a common receptor subunit for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 (Ghoreschi K. et al, Immunological Reviews, 2009, 228, 273-87). These cytokines, mediated through JAK3, are essential for the proliferation, differentiation and functions of lymphocytes. The function loss of the JAK3 kinase will result in the immunodeficiency of both human and mice. Because of the essential role of JAK3 kinase in the immune system, JAK3 kinase is a very attractive target for the treatment of immune-associated diseases, for example, autoimmune diseases like rheumatoid arthritis or allograft rejection in the patients with organ transplantation. Selective JAK3 inhibitors show significant efficacy in the clinical trials of rheumatoid arthritis.
In addition to the individual efficacy of BTK inhibitors and JAK3 inhibitors, simultaneously inhibiting both BTK pathway and JAK3 pathway will potentially have synergetic effects in clinical application. For example, via experiments, Cetkovic-Cvrlje M et al prove that the combination of using BTK and JAK3 inhibitors may improve the survival rates of animals in Graft-Versus-Host Disease (GVHD) models (Cetkovic-Cvrlje M. et al, British Journal of Haematology, 2004, 126, 821-827).
Therefore, it is necessary to develop novel compounds aiming at BTK and/or JAK3 pathways, wherein the novel compounds show good efficacy and can be orally available, which also exhibit pharmacokinetic properties favorable to the therapeutic applications and show sufficiently low toxic and side effects in vivo.